Fibrosis-related gene expression in the prostate is modulated by doxazosin treatment

[摘要] Aims: To gain new insights into the molecular mechanisms of action of doxazosin, we investigated the prostatic stroma ultrastructure and the expression of genes involved with fibrosis, such as collagen type I and III (COL1A1 and COL3A1, respectively) and TGF-beta 1, in the rat ventral prostate. Main methods: Adult Wistar rats were treated with doxazosin (25 mg/kg/day), and the ventral prostates were excised at 7 and 30 days after treatment. Untreated rats were controls. Ventral prostates were subjected to ultrastructural, immunohistochemical, biochemical and molecular analyses. Key findings: Doxazosin-treated prostates showed thickened bundles of collagen fibrils, activated fibroblasts, enlarged neurotransmitter vesicles and increased tissue immunostaining for collagen type I and type III when compared to untreated prostates. After 7 and 30 days of doxazosin treatment mRNA expression of COL1A1 and COL3A1 was significantly increased and reduced, respectively, compared to the control group. TGF-beta 1 mRNA and protein levels were increased after 7 days of doxazosin treatment, whereas only mRNA levels remained increased after 30 days of treatment. Significance: Our data suggest that relaxation of smooth muscle cells by alpha-blockers interferes with the mechanical dynamics of the prostatic stroma extracellular matrix components, generating a pro-fibrotic effect probably via the TGF-beta 1 signaling pathway. Long term treatment with doxazosin may also lead to a reduced turnover of extracellular matrix components. Our results add to a better understanding of the molecular mechanisms behind the effects of alpha-blockade on prostatic histoarchitecture and the response to treatment for benign prostatic hyperplasia. (C) 2012 Elsevier Inc. All rights reserved.

[发布日期] 2012-12-17

[关键词] Doxazosin;Benign prostatic hyperplasia;Collagen;TGF beta-1;Alpha-adrenergic blockade;Neurotransmitter vesicles